Showers, W. M. | bioRxiv Science

bioRxiv2025

Therapy resistance in AML is mediated by cytoplasmic sequestration of the transcriptional repressor IRF2BP2

While the development of venetoclax with azacitidine (ven/aza) has improved AML therapy, drug resistance remains a major challenge. Notably, primary ven/aza-resistant AML are frequently reliant on MCL1, however, the underlying mechanisms remain unclear. Co-immunoprecipitation of MCL1 from ven/aza-resistant AML samples coupled with mass spectrometry analysis identified the transcriptional repressor Interferon Regulatory Factor 2 Binding Protein 2 (IRF2BP2) as an MCL1 binding partner. This interaction results in cytoplasmic IRF2BP2 localization and loss of transcriptional repression within ven/aza-resistant leukemic stem cells (LSC). Consequently, ven/aza-resistant LSC have increased IRF2BP2 target gene expression, including acyl-CoA synthetase long-chain family member 1 (ACSL1), an essential rate-limiting enzyme for fatty acid oxidation (FAO). Inhibition of ACSL1 functionally impaired ven/aza-resistant LSC through a depletion of long-chain acyl-carnitine metabolites and FAO. Collectively, these data provide evidence for a previously undescribed mechanism by which MCL1 mediates IRF2BP2 cytoplasmic sequestration and consequent de-repression of ACSL1, thereby promoting ven/aza-resistance in AML.

cancer biology↗

bioRxiv2021

Analysis of SARS-CoV-2 Mutations Over Time Reveals Increasing Prevalence of Variants in the Spike Protein and RNA-Dependent RNA Polymerase

Amid the ongoing COVID-19 pandemic, it has become increasingly important to monitor the mutations that arise in the SARS-CoV-2 virus, to prepare public health strategies and guide the further development of vaccines and therapeutics. The spike (S) protein and the proteins comprising the RNA-Dependent RNA Polymerase (RdRP) are key vaccine and drug targets, respectively, making mutation surveillance of these proteins of great importance. Full protein sequences for the spike proteins and RNA-dependent RNA polymerase proteins were downloaded from the GISAID database, aligned, and the variants identified. Polymorphisms in the protein sequence were investigated at the protein structural level and examined longitudinally in order to identify sequence and strain variants that are emerging over time. Our analysis revealed a group of variants in the spike protein and the polymerase complex that appeared in August, and account for around five percent of the genomes analyzed up to the last week of October. A structural analysis also facilitated investigation of several unique variants in the receptor binding domain and the N-terminal domain of the spike protein, with high-frequency mutations occurring more commonly in these regions. The identification of new variants emphasizes the need for further study on the effects of these mutations and the implications of their increased prevalence, particularly as these mutations may impact vaccine or therapeutic efficacy.

bioinformatics↗